Biheteroaryl inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

This application claims the benefit of U.S. Provisional Application Ser.Nos. 60/014,592 and 60/022,586, filed Apr. 3, 1996, and Jul. 24, 1996,respectively.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other famesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also famesylated. James, et al., havealso suggested that there are famesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelirniting enzyme for the production of polyisoprenoids includingfarnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin four general classes (S. Graham, Expert Opinion Ther. Patents, (1995)5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), whilea second class of inhibitors is related to the protein substrates (e.g.,Ras) for the enzyme. Bisubstrate inhibitors and inhibitors offarnesyl-protein transferase that are non-competitive with thesubstrates have also been described. The peptide derived inhibitors thathave been described are generally cysteine containing molecules that arerelated to the CAAX motif that is the signal for protein prenylation.(Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS,88:732-736 (1991)). Such inhibitors may inhibit protein prenylationwhile serving as alternate substrates for the farnesyl-proteintransferase enzyme, or may be purely competitive inhibitors (U.S. Pat.No. 5,141,851, University of Texas; N. E. Kohl et al., Science,260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Ingeneral, deletion of the thiol from a CAAX derivative has been shown todramatically reduce the inhibitory potency of the compound. However, thethiol group potentially places limitations on the therapeuticapplication of FPTase inhibitors with respect to pharmacokinetics,pharmacodynamics and toxicity. Therefore, a functional replacement forthe thiol is desirable.

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It is, therefore, an object of this invention to develop low molecularweight compounds that will inhibit farnesyl-protein transferase andthus, the post-translational farnesylation of proteins. It is a furtherobject of this invention to develop chemotherapeutic compositionscontaining the compounds of this invention and methods for producing thecompounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises biheteroaryl-containing compounds whichinhibit the farnesyl-protein transferase. Further contained in thisinvention are chemotherapeutic compositions containing these farnesyltransferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formula A:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR2##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ and R² are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹¹ C(O)O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--;

R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R ¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO, ##STR3## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, Br, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; and

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle;

X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷ C(O)--,--C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --, provided that if a is N, then X isnot O, --C(O)NR⁷ --, --C(O)O--, --C(O)NR⁷ C(O)--, --S(O)₂ N(R¹⁰)--or--NR⁷ --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention is illustratedby the following formula A: ##STR4## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' and e' is independently N, NH,O or S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO, ##STR5## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl;

X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--, --NR⁷--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --; provided thatif a is N, then X is not O, --C(O)NR⁷ --, --S(O)₂ N(R¹⁰)-- or --NR⁷ --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention areillustrated by the formula B: ##STR6## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ --, or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

Another preferred embodiment of the compounds of this invention areillustrated by the formula C: ##STR7## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ C(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰ --or O; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula D: ##STR8##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(R¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--, provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰or O;

n is 0 or 1; provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)--, orS(O)_(m) ;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In another more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula E:##STR9## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃-C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O;

n is 0 or 1;

m is 0, or 2; and

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰ --or O;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarmesyl-protein transferase are illustrated by the formula F: ##STR10##wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH,O and S, and the remaining b, c, d and e atoms are independently CH,provided that if a is C, then at least one of b, c, d or e isindependently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--R¹⁰ --;

R⁴ is selected from H, halogen, CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ O-- or O;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula G: ##STR11##wherein: a is C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S;

R¹ is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃-C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle or C₃ -C₁₀ cycloalkyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

m is 0, 1 or 2; and

n is 0 or 1;

or the pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the invention are:

1-(5-(Thien-2'-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazole ##STR12##1-(4-Cyanobenzyl)-5-(5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyl)imidazole##STR13## or the pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. Also, combinations of substituents/or variablesare permissible only if such combinations result in stable compounds.

As used herein, "alkyl" and the alkyl portion of aralkyl and similarterms, is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms; "alkoxy" represents an alkyl group of indicated number of carbonatoms attached through an oxygen bridge.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

"Alkynyl" groups include those groups having the specified number ofcarbon atoms and having one triple bonds. Examples of alkynyl groupsinclude acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl," and the aryl portion of aralkyl, is intended tomean any stable monocyclic or bicyclic carbon ring of up to 7 members ineach ring, wherein at least one ring is aromatic. Examples of such arylelements include phenyl, naphthyl, tetrahydronaphthyl, indanyl,biphenyl, phenanthryl, antryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl,pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,thienofuryl, thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, triazolyland thienyl.

As used herein in the definition of R³, R⁴, R⁵ and R^(6a-d), the term"the substituted group" is intended to mean a substituted C₁₋₈ alkyl,substituted C₂₋₈ alkenyl, substituted C₂₋₈ alkynyl, substituted aryl orsubstituted heterocycle from which the substituent(s) R³, R⁴, R⁵ andR^(6a-e) are selected.

As used herein in the definition of R⁷, the substituted C₁₋₈ alkyl,substituted C₃₋₆ cycloalkyl, substituted aroyl, substituted aryl,substituted heteroaroyl, substituted arylsulfonyl, substitutedheteroarylsulfonyl and substituted heterocycle include moietiescontaining from 1 to 3 substituents in addition to the point ofattachment to the rest of the compound.

As used herein, when no specific substituents are set forth, the terms"substituted aryl", "substituted heterocycle" and "substitutedcycloalkyl" are intended to include the cyclic group which issubstituted on a substitutable ring carbon atom with 1 or 2substitutents selected from the group which includes but is not limitedto F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--,--OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--,(C₁ -C₆ alkyl)C(O)--, (C₁ -C₆ alkyl)OC(O)--, N₃, (C₁ -C₆alkyl)OC(O)NH--, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thienyl, furyl, isothiazolyl and C₁ -C₂₀ alkyl.

The moieties designated by the following structures ##STR14## representaromatic 5-membered heterocyclic rings and includes the following ringsystems: ##STR15## Preferably the aromatic 5-membered heterocyclic ringis selected from: ##STR16## It is understood that such ring systems maybe independently selected and that ##STR17## may be the same ordifferent in the instant compounds.

Lines drawn into the ring systems from substituents (such as from R³, R⁴etc.) means that the indicated bond may be attached to any of thesubstitutable ring carbon or nitrogen atoms.

Preferably, R¹ and R² are independently selected from: hydrogen, R¹¹C(O)O--, --N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ --, R¹⁰ O-- or unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted phenyl,--N(R¹⁰)₂, R¹⁰ O--, and R¹⁰ C(O)NR¹⁰ --.

Preferably, R³ is selected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, CN,NO₂, R¹⁰ C(O)--or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substitutent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --.

Preferably, R⁴ is selected from: hydrogen, halogen, trifluoromethyl,trifluoromethoxy and C₁ -C₆ alkyl.

Preferably, R⁵ is hydrogen.

Preferably, R^(6a), R^(6b), R^(6c) and R^(6d) are independently selectedfrom:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹S(O)_(m) --, CN, NO₂, R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substitutent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀cycloalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)-- or --N(R¹⁰)₂.

Preferably, R⁸ is independently selected from:

a) hydrogen, and

b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆perfluoroalkyl or CN.

Preferably, R⁹ is hydrogen, halogen, CF₃ or methyl.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, n and r are independently 0, 1, or 2.

Preferably s is 0.

Preferably t is 1.

It is intended that the definition of any substituent or variable (e.g.,R¹, R², R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,--N(R¹⁰)₂ represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understoodthat substituents and substitution patterns on the compounds of theinstant invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can besynthe-sized by techniques known in the art, as well as those methodsset forth below, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chroma-tography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-24, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R³, R⁶ and R⁸,as shown in the Schemes, represent the substituents R³, R⁴, R⁵, R^(6a),R^(6b), R^(6c), R^(6d) and R⁸ ; although only one such R⁶ or R⁸ ispresent in the intermediates and products of the schemes, it isunderstood that the reactions shown are also applicable when such arylor heteroaryl moieties contain multiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. Other reactions useful in the preparation of heteroarylmoieties are described in "Comprehensive Organic Chemistry, Volume 4:Heterocyclic Compounds" ed. P. G. Sammes, Oxford (1979) and referencestherein. Aryl-aryl coupling is generally described in "ComprehensiveOrganic Functional Group Transformations," Katritsky et al. eds., pp472-473, Pergamon Press (1995).

Synopsis of Schemes 1-24:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 1-14 illustrate synthesis of the instant diheteroaryl compoundwhich incorporate a preferred benzylimidazolyl sidechain. Thus, inScheme 1, for example, the commercially available dithienyl-carboxylicacid I may be reduced. The triflate of the intermediate alcohol II maybe formed in situ and coupled to a suitably substituted benzylimidazolylIII to provide, after deprotection, the instant compound IV.

Those biheteroaryl intermediates that are not commercially available maybe synthesized by methods known in the art as well as those reactionsillustrated in Schemes 2-6. Thus, as illustrated in Scheme 2 a thienylboronic acid V may be reacted under Suzuki coupling conditions (PureAppl. Chem., 63:419 (1991)) with a suitably substituted halogenatedheteroaryl moiety, such as 2-bromo, to provide the biheteroarylcarboxylic acid VI, which can then be processed as described inScheme 1. Scheme 3 illustrates the analogous series of reactionsstarting with the halogenated heteroarylaldehyde.

Scheme 4 illustrates the reaction wherein the "terminal" heteroarylmoiety is employed in the Suzuki coupling as the halogenated reactant.Such a coupling reaction is also compatible when one of the reactantsincorporates a suitably protected hydroxyl functionality as illustratedin Scheme 5.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the biheteroaryl component of the instant compounds, as shown inScheme 6. Thus, a zinc bromide adduct, such as 3-thienyl zinc bromide,may be coupled to a suitably substituted heteroaryl halide in thepresence of nickel (II) to provide the biheteroaryl VII. The heteroarylhalide and the zinc bromide adduct may be selected based on theavailability of the starting reagents.

As illustrated in Scheme 7, the sequence of coupling reactions may bemodified such that the heteroaryl-heteroaryl bond is formed last. Thus,a suitably substituted imidazole may first be alkylated with aheteroarylmethyl halide to provide intermediate VIII. Intermediate VIIIcan then undergo Suzuki type coupling to a suitably substitutedheteroaryl boronic acid.

Scheme 8 illustrates the synthesis of a thiazole containing instantcompound from the acyclic precursors. Similar strategies may be utilizedto prepare other bisheteroatom moieties.

Scheme 9 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 10 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biheteroaryl via an alkylamino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated biheteroaryl moieties to provide the instant compoundsshown.

Compounds of the instant invention wherein the A¹ (CR¹ ₂)_(n) A² (CR¹₂)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 11. The suitably substituted phenol XIVmay be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 12 illustrates an analogous series of reactions wherein the (CR²₂)_(p) X(CR² ₂)_(p) linker of the instant compounds is oxygen. Thus, asuitably substituted haloheteroaryl alcohol, such as, is reacted withmethyl N-(cyano)methanimidate to provide intermediate XVI. IntermediateXVI is then protected and, if desired to form a compound of a preferredembodiment, alkylated with a suitably protected benzyl. The intermediateXVII can then be coupled to a second heteroaryl moiety by Suzukichemistry to provide the instant compound.

Compounds of the instant invention wherein the A¹ (CR¹ ₂)_(n) A² (CR¹₂)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 13. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 1) provides the instant compound XX. If other R¹ substituents aredesired, the acetyl moiety can be manipulated as illustrated in theScheme.

Addition of various nucleophiles to an imidazolyl aldehyde may also beemployed to form a substituted alkyl linker between the biheteroarylmoiety and the preferred W (imidazolyl) as shown in Scheme 14. Thus abishalogenated five membered heteroaryl, such as 2,4-dibromothiophene,may undergo metal halogen exchange followed by reaction with a suitablysubstituted imidazolyl aldehyde and acteylation to form a regioisomericmixture of the acetyl intermediates. The halogenated regioisomericmixture may be chromatographically separated at this stage, ifconvenient. Suzuki coupling with a suitably substituted 5-memberedheteroaryl boronic acid affords the instant acetoxy compound, which canbe treated with lithium hydroxide to remove the acetyl group. Then,similar substituent manipulation as shown in Scheme 13 may be performedon a fully functionalized compound which incorporates an R² hydroxylmoiety. ##STR18##

Schemes 15-24 illustrate reactions wherein the moiety ##STR19##incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other biheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes. Thealdehydes can be prepared by standard procedures, such as that describedby O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses,1988, 67, 69-75, from the appropriate amino acid (Scheme 15). Metalhalogen exchange chemistry (Scheme 14) may be employed when manipulatingthe aldehydes. Alternatively, Grignard chemistry may be utilized, asshown in Scheme 15. Thus, Suzuki coupling provides, for example, thepyrrole containing biheteroaryl XXI. Reaction of the intermediate XXIwith a Grignard reagent provides the N-pyrrylmagnesium derivative XXIa,which is then reacted with an aldehyde to provide the C-alkylatedinstant compound XXII. The product XXII can be deoxygenated by methodsknown in the art, such as a catalytic hydrogention, then deprotectedwith trifluoroacetic acid in methylene chloride to give the finalcompound XXIIa. The final product XXII may be isolated in the salt form,for example, as a trifluoroacetate, hydrochloride or acetate salt, amongothers. The product diamine XXII can further be selectively protected toobtain XXIII, which can subsequently be reductively alkylated with asecond aldehyde to obtain XXIV. Removal of the protecting group, andconversion to cyclized products such as the dihydroimidazole XXV can beaccomplished by literature procedures.

Scheme 16 illustrates the use of in situ formation of a lithium anion ofa suitably substituted N-alkyl pyrrole to provide the C-alkylatedcompound of the instant invention.

If the biheteroaryl subunit is reductively alkylated with an aldehydewhich also has a protected hydroxyl group, such as XXVI in ReactionScheme 17, the protecting groups can be subsequently removed to unmaskthe hydroxyl group (Reaction Schemes 17, 18). The alcohol can beoxidized under standard conditions to e.g. an aldehyde, which can thenbe reacted with a variety of organometallic reagents such as Grignardreagents, to obtain secondary alcohols such as XXX. In addition, thefully deprotected amino alcohol XXXI can be reductively alkylated (underconditions described previously) with a variety of aldehydes to obtainsecondary amines, such as XXXII (Reaction Scheme 18), or tertiaryamines.

The Boc protected amino alcohol XXVIII can also be utilized tosynthesize 2-aziridinylmethylbiheteroaryl such as XXXIII (ReactionScheme 19). Treating XXVIII with 1,1'-sulfonyldiimidazole and sodiumhydride in a solvent such as dimethylformamide led to the formation ofaziridine XXXIII. The aziridine is reacted with a nucleophile, such as athiol, in the presence of base to yield the ring-opened product XXXIV.

In addition, the biheteroaryl subunit can be reacted with aldehydesderived from amino acids such as O-alkylated tyrosines, according tostandard procedures, to obtain compounds such as XL, as shown inReaction Scheme 20. When R' is an aryl group, XL can first behydrogenated to unmask the phenol, and the amine group deprotected withacid to produce XLI. Alternatively, the amine protecting group in XL canbe removed, and O-alkylated phenolic amines such as XLII produced.

Schemes 21-24 illustrate syntheses of suitably substituted aldehydesuseful in the syntheses of the instant compounds wherein the variable Wis present as a pyridyl moiety. Similar synthetic strategies forpreparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art. ##STR20##

The instant compounds are useful as pharmaceutical a gents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas activity (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) or byother mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal,2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/g of body weight per day, preferably of between 0.5 mg/g of bodyweight to about 40 mg/g of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase to famesylatethe substrate, the chemical content of the assay mixtures may bedetermined by well known immuno-logical, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 1

1-(5-(Thien-2'-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetic acid salt

Step A: 1-Trityl-4-(4-cyanobenzyl)-imidazole

To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reactionstirred under argon for 45 minutes, at 20° C. The suspension was cooledto 0° C. and a-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 mL)was added dropwise over a period of 10 minutes. The reaction was thenallowed to stir at 20° C. for 6 hours and bis(triphenylphosphine)NickelII chloride (2.40 g, 3.64 mmol) and 4-iodotritylimidazole (15.95 g, 36.6mmol) were added in one portion. The resulting mixture was stirred 16hours at 20° C. and then quenched by addition of saturated NH₄ Clsolution (100 mL) and the mixture stirred for 2 hours. Saturated aq.NaHCO₃ solution was added to give a pH of 8 and the solution wasextracted with EtOAc (2×250 mL), dried (MgSO₄) and the solventevaporated in vacuo. The residue was chromatographed (Silica gel, 0-20%EtOAc inCH₂ Cl₂) to afford the title compound as a white solid.

¹ H NMR (CDCl₃, 400 Mz) δ (7.54 (2H, d, J=7.9 Hz), 7.38(1H, s),7.36-7.29 (11H, m), 7.15-7.09(6H, m), 6.58(1H, s) and 3.93(2H, s) ppm.

Step B: 5-(Thien-2-yl)-thiophene-2-carboxaldehyde

To a solution of thien-2-ylboronic acid (0.939 g, 7.34 mmol) and Na₂ CO₃(2.40 g, 22.6 mmol) in water (75 mL) is added p-dioxane (75 mL). Thismixture is treated sequentially with 5-carboxy-2-thiophenecarboxaldehyde(1.43 g, 7.48 mmol) and palladium (II) acetate (151 mg, 0.673 mmol) andallowed to stir at ambient temperature for 16 hours. The solvent isevaporated in vacuo. To the residue is added EtOAc (400 mL) and water(300 mL). The aqueous layer is acidified to pH 1 with 1.0N aq. HCl. Theaqueous layer is extracted with EtOAc (2×200 mL). The organic extractsare combined, washing with brine (200 mL), 5% aq. Na₂ S₂ O₃ (200 mL),sat. aq. NaCl (200 mL), drying (Na₂ SO₄), and the solvent evaporation invacuo affords the title compound.

Step C: 5-(Thien-2-yl)-2-hydroxymethylthiophene

To a solution of 5-(thien-2'-yl)-thiophen-2-ylcarboxaldehyde (1.11 g,5.73 mmol) in THF (25 mL) at 0° C. is added 1.0M lithium aluminumhydride in tetrahydrofuran (12.0 mL, 12.0 mmol) over 10 minutes. Thereaction is allowed to stir at ambient temperature for 3 hours. Thereaction is cooled to 0° C., and water (0.5 mL), 4N aq. NaOH (0.5 mL),and water (1.5 mL) are added sequentially. The reaction is filteredthrough a pad of Celite and the filtrate is evaporated in vacuo. Theresidue is chromatographed to afford the title compound.

Step D: 1-(5-(Thien-2-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazoletrifluoroacetic acid salt

To a solution of 5-(thien-2-yl)-2-hydroxymethyl thiophene (283 mg, 1.44mmol) and diisopropylethylamine (0.260 mL, 1.49 mmol) in dichloromethane(6.0 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.250mL, 1.49 mmol) and the mixture stirred at -78° C. for 1 hour. To thismixture is added a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (613mg, 1.44 mmol) in dichloromethane (6.0 mL). The mixture is allowed towarm to ambient temperature and stirred for 2 hours. The solvent isevaporated in vacuo. The residue is dissolved in methanol (15 mL),heated at reflux for 1 hour, and the solvent is evaporated in vacuo. Theresidue is partitioned between CH₂ Cl₂ and sat. aq. NaHCO₃ solution. Theorganic layer is dried, (Na₂ SO₄) and the solvent is evaporated invacuo. The residue is purified by preparative HPLC, (gradient elution,95:5 to 5:95% water:acetonitrile containing 0.1% trifluoroacetic acid)to afford the title compound as a trifluoroacetic acid salt.

Example 2

1-(4--Cyanobenzyl)-5-(5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyl)imidazole

Step A: 1H-Imidazole-4-acetic acid methyl ester hydrochloride

A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6mmol) in methanol (100 mL) was saturated with gaseous hydrogen chloride.The resulting solution was allowed to stand at room temperature for 18hours. The solvent was evaporated in vacuo to afford the title compoundas a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 8.85(1H, s), 7.45(1H, s), 3.89(2H, s) and3.75(3H, s) ppm.

Step B: 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester

To a solution of the product from Step A (24.85 g, 0.141 mol) in DMF(115 mL) was added triethylamine (57.2 mL, 0.412 mol) andtriphenylmethyl bromide (55.3 g, 0.171 mol) and the suspension wasstirred for 24 hours. After this time, the reaction mixture was dilutedwith EtOAc and water. The organic phase was washed with sat. aq. NaHCO₃,dried, (Na₂ SO₄) and the solvent evaporated in vacuo. The residue waspurified by chromatography (Silica gel, 0-100% EtOAc in hexanes) toprovide the title compound as a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.35(1H, s), 7.31(9H, m), 7.22(6H, m),6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.

Step C: 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetic acid methyl ester

To a solution of the product from Step B (8.00 g, 20.9 mmol) inacetonitrile (70 mL) was added 4-cyanobenzyl bromide (4.10 g, 20.92mmol) and heated at 55° C. for 3 hours. The reaction was cooled to roomtemperature and the resulting imidazolium salt was collected byfiltration. The filtrate was heated at 55° C. for 18 hours. The reactionmixture was cooled to room temperature and evaporated in vacuo. To theresidue was added EtOAc (70 mL) and the resulting precipitate collectedby filtration. The precipitated imidazolium salts were combined,suspended in methanol (100 mL) and heated to reflux for 30 minutes.After this time, the solvent was removed in vacuo. The resulting residuewas suspended in EtOAc (75 mL) and the solid isolated by filtration andwashed with EtOAc. The solid was treated with sat. aq. NaHCO₃ solution(300 mL) and CH₂ Cl₂ (300 mL) and stirred at room temperature for 2hours. The organic layer was separated, dried, (MgSO₄) and evaporated invacuo to afford the title compound as a white solid

1HNMR (CDCl₃, 400 MHz) δ 7.65(1H, d, J=8 Hz), 7.53(1H, s), 7.15(1H, d,J=8 Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: 4- 5-(Aminocarbonylmethyl)imidazol-1-ylmethyl!benzonitrile

To a 100 mL glass pressure vessel with a stirring bar was added1-(4--Cyanobenzyl)-1H-imidazol-5-yl!acetic acid methyl ester (6.00 g,23.5 mmol) and absolute ethanol (50 mL). This well stirred solution wascooled to -78° C. and 50 mL of anhydrous ammonia was condensed in. Thevessel was sealed and the mixture warmed to ambient temperature. Thissolution was stirred 24 hours at ambient temperature. The excess ammoniawas allowed to evaporate and the ethanol was removed in vacuo. The solidresidue was triturated with EtOAc and collected on a frit. This materialwas dried in vacuo to give the title compound as a white solid. ¹ H NMR(DMSO-d₆, 400 MHz) δ 3.25(s, 2H), 5.32(s, 2H), 6.88(s, 1H), 6.96(s, 1H),7.24(d, j=8 Hz,2H), 7.42(s,1H), 7.68(s,1H), 7.83(d, j=8 Hz, 2H).

Step E: 1-(4-Cyanobenzyl)-5-(aminothiocarbonyl)methyl-1H-imidazole

To a 50 mL round bottomed flask with a stirring bar, reflux condenserand an argon inlet was added 4-5-(aminocarbonyl-methyl)imidazol-1-ylmethyl!benzonitrile (0.36 g, 1.49mmol), Lawesson's reagent (0.73 g, 1.8 mmol) and 1,4-dioxane (10 mL).This well stirred mixture was heated at 80° C. for 24 hours. The cooledreaction mixture was concentrated in vacuo and the residue waschromatographed (silica gel, 10% 2-propanol in ammonia saturated CHCl₃).The title compound was obtained as a yellow, crystalline solid.

¹ H NMR (DMSO-d₆, 400 MHz) δ 3.66(s, 2H), 5.41(s, 2H), 6.85(s, 1H),7.24(d, j=8 Hz,2H), 7.70(s,1H), 7.82(d, j=8 Hz, 2H), 9.21(s, 1H),9.56(s, 1H).

Step F: 1-(4-Cyanobenzyl)-5-5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyl!imidazole

To a 25 mL round bottomed flask with a stirring bar reflux condenser andan argon inlet is added1-(4-cyanobenzyl)-5-(aminothiocarbonyl)methyl-1H-imidazole (0.12 g,0.468 mmol), dry THF (10 mL), and N-methyl-a-bromoacetylpyrrole (0.098g, 0.491 mmol). This mixture is heated at 50° C. for 7 hours. The cooledreaction mixture is diluted with EtOAc and washed sucessively with aq.NaHCO₃, water, and brine. The organic extract is dried, (MgSO₄) and thesolvent is evaporated in vacuo. The residue is purified bychromatography to afford the title compound.

Example 3

In vitro inhibition of ras farnesyl transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al, Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine--N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5mM dithiothreitol (DTT), 100 mM ³ H!-farnesyl diphosphate ( ³ H!-FPP;740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTaseat 31° C. for 60 min. Reactions were initiated with FPTase and stoppedwith 1 ml of 1.0M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvester, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the ³ H!-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention are tested for inhibitoryactivity against human FPTase by the assay described above.

Example 4

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemeted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfamesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 5

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR21## wherein: a is N or C;from 0-4 ofb, c, d and e are independently N, NH, O and S, and the remaining b, c,d and e atoms are independently CH, provided that if a is C, then atleast one of b, c, d or e is independently N, NH, O or S; a' is N or C;from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S; R¹ and R² are independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹¹ C(O)O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--; R³, R⁴ and R⁵ are independently selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c) and R^(6d) are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R⁷is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:a) C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d)HO, ##STR22## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or h) C₁₋₄ perfluoroalkyl; R⁸ isindependently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, cyanophenyl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹⁰ OC(O)NH--; provided that when R⁸ is heterocycle,attachment of R⁸ to V is through a substitutable ring carbon; R⁹ isindependently selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, Br, R¹¹ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a) hydrogen, b)heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atomsare replaced with a a heteroatom selected from O, S, and N, and e) C₂-C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m) and V isnot hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided thatwhen V is heterocycle, attachment of V to R⁸ and to A¹ is through a ringcarbon; W is a heterocycle; X is a bond, --CH═CH--, O, --C(═O)--,--C(O)NR⁷ --, --NR⁷ C(O)--, --C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--,--NR⁷ --, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --, providedthat if a is N, then X is not O, --C(O)NR⁷ --, --C(O)O--, --C(O)NR⁷C(O)--, --S(O)₂ N(R¹⁰)-- or --NR⁷ --; m is 0, 1 or 2; n is independently0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3;r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1 of the formula A: ##STR23## wherein: a is N or C;from 0-4 ofb, c, d and e are independently N, NH, O and S, and the remaining b, c,d and e atoms are independently CH, provided that if a is C, then atleast one of b, c, d or e is independently N, NH, O or S; a' is N or C;from 0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S; R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl,R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl; R² is independently selectedfrom:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³, R⁴ and R⁵ areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl; d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl,heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) aryl orheterocycle, c) halogen, d) HO, ##STR24## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or h)C₁₋₄ perfluoroalkyl; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon; R⁹ is selected from:a) hydrogen, b) C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)----C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a ring carbon; Wis a heterocycle selected from pyrrolidinyl, imnidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl; X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;provided that if a is N, then X is not O, --C(O)NR⁷ --, --S(O)₂N(R¹⁰)--or --NR⁷ --; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4;p is independently 0, 1, 2, 3 or 4; q is 0,1,2 or 3; r is 0 to 5,provided that r is 0 when V is hydrogen; and t is 0 or 1; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 of the formula B: ##STR25## wherein: a is N or C;from 0-4 of b,c, d and e are independently N, NH, O and S, and the remaining b, c, dand e atoms are independently CH, provided that if a is C, then at leastone of b, c, d or e is independently N, NH, O or S; a' is N or C; from0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S; R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl,R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl; R² is independently selectedfrom:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³ and R⁴ areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ C(O)--NR¹⁰ --;R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon; R^(9a) and R^(9b) are independentlyhydrogen, C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a ring carbon; Xis a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--; provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰--, or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4;and r is 0 to 5, provided that r is 0 when V is hydrogen; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1 of the formula C: ##STR26## wherein: a is N or C;from 0-4 of b,c, d and e are independently N, NH, O and S, and the remaining b, c, dand e atoms are independently CH, provided that if a is C, then at leastone of b, c, d or e is independently N, NH, O or S; a' is N or C; from0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S; R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl,R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl; R² is independently selectedfrom:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³ and R⁴ areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon; R^(9a) and R^(9b) are independentlyhydrogen, C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a ring carbon; Xis a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--; provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰-- or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4,provided that p is not 0 if X is a bond, --NR¹⁰ -- or O; and r is 0 to5, provided that r is 0 when V is hydrogen; or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 3 of theformula D: ##STR27## wherein: a is N or C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that if a is C, then at least one of b, c, dor e is independently N, NH, O or S; a' is N or C; from 0-4 of b', c',d' and e' are independently N, NH, O and S, and the remaining b', c', d'and e' atoms are independently CH, provided that if a' is C, then atleast one of b', c', d' or e' is independently N, NH, O or S; R¹ isindependently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R³ is selected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃; R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR11OC(O)--NR¹⁰ --; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon; R^(9a) and R^(9b) are independentlyhydrogen, halogen, CF₃ or methyl; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A¹ is selectedfrom: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; X is a bond,--CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, NR¹⁰ --, O or --C(═O)--,provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O; nis 0 or 1; provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)--, orS(O)_(m) ; m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4; or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 4 of the formula E: ##STR28## wherein: a is N or C;from 0-4 of b,c, d and e are independently N, NH, O and S, and the remaining b, c, dand e atoms are independently CH, provided that if a is C, then at leastone of b, c, d or e is independently N, NH, O or S; a' is N or C; from0-4 of b', c', d' and e' are independently N, NH, O and S, and theremaining b', c', d' and e' atoms are independently CH, provided that ifa' is C, then at least one of b', c', d' or e' is independently N, NH, Oor S; R¹ is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂,F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R² is independently selectedfrom:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃; R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a ring carbon; R^(9a) and R^(9b) are independentlyhydrogen, halogen, CF₃ or methyl; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond,--CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or --C(═O)--;provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O; nis 0 or 1; m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p isnot 0 if X is a bond, --NR¹⁰ -- or O; or a pharmaceutically acceptablesalt thereof.
 7. The compound according to claim 5 of the formula F:##STR29## wherein: a is N or C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that if a is C, then at least one of b, c, dor e is independently N, NH, O or S; a' is N or C; from 0-4 of b', c',d' and e' are independently N, NH, O and S, and the remaining b', c', d'and e' atoms are independently CH, provided that if a' is C, then atleast one of b', c', d' or e' is independently N, NH, O or S; R¹ isindependently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F, c) C₁ -C₆alkyl unsubstituted or substituted by aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, CH₃ and CF₃ ;R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or --C(═O)--; provided thatif a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O; m is 0, 1 or 2;and p is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.8. The compound according to claim 6 of the formula G: ##STR30##wherein: a is C;from 0-4 of b, c, d and e are independently N, NH, O andS, and the remaining b, c, d and e atoms are independently CH, providedthat if a is C, then at least one of b, c, d or e is independently N,NH, O or S; a' is N or C; from 0-4 of b', c', d' and e' areindependently N, NH, O and S, and the remaining a', c', d' and e' atomsare independently CH, provided that if a' is C, then at least one of b',c', d' or e' is independently N, NH, O or S; R¹ is independentlyselected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle or C₃ -C₁₀ cycloalkyl, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, CH₃ and CF₃ ;R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; A¹ is selected from: a bond,--C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; m is 0, 1 or 2; and n is 0 or 1;or the pharmaceutically acceptable salts thereof.
 9. A compound whichinhibits farnesyl-protein transferase whichis:1-(5-(thlien-2-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazole##STR31## 1-(4-Cyanobenzyl)-5-(5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyl)imidazole ##STR32## or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 1. 11. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 3. 12. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 4. 13. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 9. 14. A method for inhibitingfarnesyl-protein transferase which comprises administering to a mammalin need thereof a therapeutically effective amount of a composition ofclaim
 10. 15. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 11. 16. A method forinhibiting farnesyl-protein transferase which comprises administering toa mammal in need thereof a therapeutically effective amount of acomposition of claim
 12. 17. A method for inhibiting farnesyl-proteintransferase which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 13. 18. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 10. 19. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim
 11. 20. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 12. 21. A method for treatingcancer which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 13. 22. Amethod for treating neurofibromin benign proliferative disorder whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 10. 23. A method for treatingblindness related to retinal vascularization which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 10. 24. A method for treatinginfections from hepatitis delta and related viruses which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 10. 25. A method for preventingrestenosis which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 10. 26. Amethod for treating polycystic kidney disease which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 10. 27. A pharmaceutical compositionmade by combining the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 28. A process for making a pharmaceuticalcomposition comprising combining a compound of claim 1 and apharmaceutically acceptable carrier.